Cytochrome c lysine acetylation regulates cellular respiration and cell death in ischemic skeletal muscle

Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc...

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Detalles Bibliográficos
Autores: Morse, Paul T, Pérez-Mejías, Gonzalo, Wan, Junmei, Turner, Alice A, Márquez, Inmaculada, Kalpage, Hasini A, Vaishnav, Asmita, Zurek, Matthew P, Huettemann, Philipp P, Kim, Katherine, Arroum, Tasnim, Rosa, Miguel A. de la, Chowdhury, Dipanwita Dutta, Lee, Icksoo, Brunzelle, Joseph S, Sanderson, Thomas H, Malek, Moh H, Meierhofer, David, Edwards, Brian F P, Díaz-Moreno, Irene, Hüttemann, Maik
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/354698
Acceso en línea:http://hdl.handle.net/10261/354698
https://api.elsevier.com/content/abstract/scopus_id/85164843565
Access Level:acceso abierto
Palabra clave:lysine
skeletal muscle
acetylation
Cytochrome c
Descripción
Sumario:Skeletal muscle is more resilient to ischemia-reperfusion injury than other organs. Tissue specific post-translational modifications of cytochrome c (Cytc) are involved in ischemia-reperfusion injury by regulating mitochondrial respiration and apoptosis. Here, we describe an acetylation site of Cytc, lysine 39 (K39), which was mapped in ischemic porcine skeletal muscle and removed by sirtuin5 in vitro. Using purified protein and cellular double knockout models, we show that K39 acetylation and acetylmimetic K39Q replacement increases cytochrome c oxidase (COX) activity and ROS scavenging while inhibiting apoptosis via decreased binding to Apaf-1, caspase cleavage and activity, and cardiolipin peroxidase activity. These results are discussed with X-ray crystallography structures of K39 acetylated (1.50 Å) and acetylmimetic K39Q Cytc (1.36 Å) and NMR dynamics. We propose that K39 acetylation is an adaptive response that controls electron transport chain flux, allowing skeletal muscle to meet heightened energy demand while simultaneously providing the tissue with robust resilience to ischemia-reperfusion injury.

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